AREA B: PRECISE DCE-MRI OF BRAIN TUMORS PROJECT SUMMARY This project will develop and validate an improved dynamic contrast-enhanced (DCE) MRI technique for assessing brain tumor response to therapy. Rationale: Historically, increases in tumor size or enhancement have signified tumor progression, and decreases in tumor size have signified treatment response. With the advent of novel chemotherapy agents, including immunotherapy, simple changes in size or enhancement are no longer sufficient to make treatment decisions. We believe that improved DCE-MRI methods can provide new and powerful biomarkers to image brain tumors and detect early response to therapy. This will enhance our ability to prolong survival in a higher proportion of brain tumor patients traditionally regarded as the most dire prognostic group (including recurrent high-grade glioma and metastatic melanoma), who are often left out of clinical trials due to very short life expectancy. Innovation: We propose Specially Tailored Acquisition and Reconstruction (STAR) DCE-MRI, in which acquisition and reconstruction are tailored from an estimation- theoretic point of view to create the most accurate and reproducible tracer kinetic (TK) parameter maps, unlike conventional approaches that optimize the quality of intermediate images. We will fully integrate TK models with DCE-MRI acquisition and reconstruction. Our preliminary data shows 36-fold improvement in spatial resolution and coverage compared to current techniques, with no loss of image quality in brain tumor patients; and we expect to only get better. Compared to current state-of-the-art DCE-MRI, this technique will provide three major advances: 1- exquisite (sub-1 mm isotropic) spatial resolution to quantitatively assess narrow tumor margins and small lesions, 2- whole-brain coverage including all lesions and all surrounding tissue thereby simplifying the exam, 3- robust measurement of patient specific arterial inputs which are required for accurate contrast agent kinetic modeling. Approach: We will optimize, technically validate, and clinically evaluate STAR DCE-MRI method that provides improved quantitative parametric brain maps including blood- brain barrier leakage and fractional plasma volume. Specifically, we will: 1- optimize and technically validate STAR DCE-MRI to produce accurate and reproducible TK parameter maps, 2- produce a robust clinical implementation of STAR DCE-MRI, and 3- clinically evaluate STAR DCE-MRI in patients with brain tumors, specifically those with recurrent high-grade glioma treated with an anti-angiogenic agent, and those with brain melanoma metastases treated with an immunotherapy agent. Broader Impact: Improved quantitative multi- parametric DCE-MRI has a potential role in the assessment of all neurologic diseases that have a microvascular component. This technical work, particularly leveraging specific nonlinear temporal models during image reconstruction, is likely to have implications for DCE-MRI of prostate, renal, breast, and liver tumors as well as outside of DCE-MRI. Importantly it addresses a critical unmet need in oncology in providing a robust, reproducible, high spatio-temporal resolution and high spatial coverage biomarker as a potential end point for clinical trials of novel therapeutic agents in cancer research.